Synthesis and Biological Evaluation of Carbazole Aminoalcohols as Antitumor Agents

A series of racemic and chiral carbazole aminoalcohols were synthesized and evaluated of their antitumor activities. The heterocycle, substitution site, length of alkyl chain as well as chirality were proved to interfere the topoisomerase I (topo I) inhibition activities. Carbazole aminoalcohols with potent topo I inhibition activities, like pyrrolidine derivative 5 and propyl- to pentyl- amines derivatives 7, 14, 15 and 24, were proved to exhibit good antitumor activities with IC(50)s in the single digit micromolar range against cancer cell lines A549, HCT116, and MDA-MB-231. Meanwhile, the hexyl- to decyl- amines substituted carbazole aminoalcohols (16-22), though not showing good topo I inhibition activities, were also found to have potent antitumor activities. Further research proved that the representative compound 16 had broad-spectrum antitumor activities against 15 cancer cell lines from various organs with IC(50)s at 1.5 - 7.9 mu M and induced apoptosis-inducing activities in leukemia cell lines. In in vivo studies, 16 inhibits the tumor growth in OCI-AML2 xenograft model with TGI = 43%. Bcl-2 was proved to involve in compound 16 induced apoptosis.